Pharmacokinetics and tissue distribution study of two novel quinazoline PI3K/mTOR dual-inhibitors, potential anticancer agents.

S1 and S2, two structurally similar quinazoline derivatives, are novel anticancer drugs targeting the PI3K/AKT/mTOR signaling pathway channel. However, their pharmacokinetic and tissue distribution characteristics are unknown, which has hindered further development and in-depth studies. In this study, a simple, rapid and sensitive method using high performance liquid chromatography was established and validated to quantitatively study the pharmacokinetics and tissue distribution profiles of S1 and S2 in rats following intravenous injection. The results indicated that after intravenous injection, the elimination of S1 and S2 fit the two-compartment model and linear pharmacokinetics characteristics were observed. Furthermore, S1 and S2 were widely distributed and found in high concentrations in liver and kidney tissues and a small proportion of S1 and S2 could cross the blood-brain barrier and be distributed in the brain. The current findings will contribute to interpretation and understanding the relationship between dosage and pharmacodynamic effects of S1 and S2.

Study on the interaction of two quinazoline derivatives as novel PI3K/mTOR dual inhibitors and anticancer agents to human serum albumin utilizing spectroscopy and docking.

Interactions of human serum albumin (HSA) with two structurally similar quinazoline derivatives, S1 and S2 , which are potential anticancer drugs acting on PI3K/mTOR targets, were investigated in vitro utilizing multiple spectroscopy as well as molecular docking. The fluorescence quenching study demonstrated that HSA fluorescence could be statically quenched by S1 and S2 through the formation of an HSA-drug complex. Furthermore, the details of the binding site number, binding constant, as well as the thermodynamic parameters, were estimated at 298, 303, and 310 K. The results revealed that hydrogen bond interactions, as well as van der Waals forces, were the predominant factors responsible for binding HSA to S1 or S2 . Synchronous fluorescence and ultraviolet (UV) absorption spectra suggested that S1 and S2 had little effect on the polarity of the microenvironment and conformation of HSA. Energy transfer from HSA to S1 or S2 most probably occurred. The docking study revealed that S1 and S2 were able to bind to the hydrophobic cavity that was located in the HSA subdomain IIA and formed varying numbers of hydrogen bonds with amino acid residues nearby. Due to the subtle difference in the chemical structure, the binding of S1 and S2 to HSA was slightly different.

Long non-coding RNA metastasis-related lung adenocarcinoma transcript 1 (MALAT1) forms a negative feedback loop with long non-coding RNA colorectal neoplasia differentially expressed (CRNDE) in sepsis to regulate lung cell apoptosis.

It has been reported that long non-coding RNAs (lncRNAs) metastasis-related lung adenocarcinoma transcript 1 (MALAT1) and colorectal neoplasia differentially expressed (CRNDE) play opposite roles in sepsis. Therefore, we explored their potential interaction with sepsis. To this end, we determined MALAT1 and CRNDE levels using RT-qPCR in plasma samples collected from healthy controls (n = 60) and sepsis patients (n = 60) before and after treatment and the effects of MALAT1 and CRNDE overexpression in human bronchial epithelial cells (HBEpCs) on the expression of each other and HBEpC apoptosis. RT-qPCR analyses showed that MALAT1 was upregulated, while CRNDE was downregulated in sepsis and overexpression of MALAT1 and CRNDE downregulated the expression of each other. After proper treatment, MALAT1 was downregulated and CRNDE was upregulated in sepsis. Lipopolysaccharides (LPS) treatment of HBEpCs upregulated MALAT1 and downregulated CRNDE. Cell apoptosis analysis showed that MALAT1 overexpression promoted, while CRNDE overexpression inhibited LPS-induced HBEpC apoptosis. Moreover, CRNDE overexpression attenuated the effects of MALAT1 overexpression. Overall, MALAT1 might form a negative feedback loop with CRNDE in sepsis to regulate lung cell apoptosis.

Protective ballooning technique for prevention of side branch occlusion in coronary nonleft main true bifurcation lesions: A single-center study.

OBJECTIVES: We aimed to evaluate the efficacy of a protective ballooning technique in preventing side branch (SB) occlusion and to assess the long-term clinical outcomes for coronary nonleft main true bifurcation lesions. BACKGROUND: SB occlusion is a major complication associated with percutaneous coronary intervention (PCI) for coronary bifurcation lesions. METHODS: Patients were consecutively enrolled and randomly assigned to protective ballooning technique or jailed wire technique group. Periprocedural and long-term clinical outcomes were compared. RESULTS: Patients in the protective ballooning technique (n = 173) and jailed wire technique (n = 167) groups were followed up for 12 months. SB occlusion occurred in one patient (0.6%) and nine patients (5.4%) in each group, respectively. The proportion of thrombolysis in myocardial infarction (TIMI) flow grade 3 of the SB was higher in the protective ballooning technique group (98.8% vs. 95.2%, p < 0.05). SB rewiring was necessary in one patient in the protective ballooning technique group (0.6%) with provisional stenting, significantly lower than that in the jailed wire technique group (seven patients, 4.2%; p = 0.03). Periprocedural myocardial infarction occurred in three (1.73%) and six (3.59%) patients in the protective ballooning technique and jailed wire technique groups without significant difference, respectively. Major adverse cardiovascular events at 12 months were similar in both groups. CONCLUSIONS: Protective ballooning technique is effective for the prevention of SB occlusion in nonleft main true bifurcation lesions and had favorable long-term outcomes at the 12-month follow-up.

Effectiveness and safety of pyrotinib-based therapy in patients with HER2-positive metastatic breast cancer: A real-world retrospective study.

The previous studies had demonstrated the promising effectiveness and acceptable safety of pyrotinib in patients with HER2-positive metastatic breast cancer. We aimed to investigate the real-world data of pyrotinib in complex clinical practice and complement the findings of clinical trials. Two hundred and eighteen patients were included for effectiveness analysis. A total of 62.0% had received two or more lines of systematic therapy, and 95.4% had been exposed to prior anti-HER2 therapy, with 95.4% receiving trastuzumab, 5.0% receiving pertuzumab, and 40.8% receiving lapatinib. The median progression-free survival (PFS) was 9.3 months and the objective response rate (ORR) was 44.0%. Patients treated with pyrotinib-based therapy as first, second, or later line had a median PFS of 15.0, 10.3, and 6.8 months, respectively. Patients treated with pyrotinib and trastuzumab received significant benefit in terms of median PFS compared with pyrotinib alone (10.7 (9.1-12.3) vs. 8.8 (8.1-9.5), p = 0.016). Patients pretreated with lapatinib had a median PFS of 6.9 months. The median PFS time was 7.0 months in patients with brain metastasis. Multivariate Cox regression analyses showed that lines of pyrotinib-based therapy (1 vs. 2 vs. ≥3), prior treatment with lapatinib, and combination treatments with trastuzumab proved to be independent predictors of PFS. Two hundred and forty-eight patients were included in the safety analysis, and the results showed that the toxicity of pyrotinib was tolerable, with the most common grade 3/4 adverse event being diarrhea (19.8%). Pyrotinib-based therapy demonstrated promising efficacy and tolerable toxicity in first-, second-, and later-line treatments and in lapatinib-treated patients. The combination of pyrotinib and trastuzumab showed advantages in PFS, even for patients resisting trastuzumab. Pyrotinib-based therapy could be the preferred choice for brain metastasis patients, especially when combined with brain radiotherapy.

1,3-Benzodioxole-based fibrate derivatives as potential hypolipidemic and hepatoprotective agents.

A series of target compounds 1,3-benzodioxole-based fibrate derivatives were designed and synthesized. All the target compounds were preliminarily evaluated by hyperlipidemia mice induced by Triton WR-1339, in which compound 12 displayed a greater anti-hyperlipidemia activity than other compounds as well as positive drug fenofibrate (FF). 12 showed a significant reduction of plasma lipids, such as triglycerides (TG), total cholesterol (TC) and low-density lipoprotein cholesterin (LDL-C), in high fat diet (HFD) induced hyperlipidemic mice. In addition, hepatic transaminases (AST and ALT) were ameliorated after administration of 12, in particular the AST, and the histopathological examination showed that 12 improved the hepatic lipid accumulation. The expression of PPAR-α involved in lipids metabolism was up-regulated in the liver tissues of 12-treated group. Other significant activity such as antioxidant, and anti-inflammation was confirmed and reinforced the effects of 12 as a potential hypolipidemia and hepatoprotective agent.

miR-92a-3p promotes ox-LDL induced-apoptosis in HUVECs via targeting SIRT6 and activating MAPK signaling pathway.

Atherosclerosis could be induced by multiple factors, including hypertension, hyperlipidemia, and smoking, and its pathogenesis has not been fully elucidated. MicroRNAs have been shown to possess great anti-atherosclerotic potential, but the precise function of miR-92a-3p in atherosclerosis and its potential molecular mechanism have not been well clarified. Flow cytometry assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazol-3-ium bromide (MTT) assay were performed to evaluate effects of oxidized low-density lipoprotein (ox-LDL) on proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs), respectively. Malondialdehyde and superoxide dismutase levels in cell lysate were assessed with biochemical kits. The expression levels of miR-92a-3p and Sirtuin6 (SIRT6) in HUVECs exposed to ox-LDL were estimated by real-time quantitative polymerase chain reaction (RT-qPCR). In addition, the protein levels of SIRT6, c-Jun N-terminal kinase (JNK), phosphorylation JNK (p-JNK), p38 mitogen activated protein kinase (p38 MAPK), and phosphorylation p38 MAPK (p-p38 MAPK) were measured by western blot assays. The relationship between miR-92a-3p and SIRT6 was confirmed by dual-luciferase reporter assay. Ox-LDL induced apoptosis and oxidative stress in HUVECs in concentration- and time-dependent manners. Conversely, miR-92a-3p silencing inhibited apoptosis and SIRT6 expression in HUVECs. The overexpression of miR-92a-3p enhanced apoptosis and phosphorylation levels of JNK and p38 MAPK as well as inhibited proliferation in ox-LDL-induced HUVECs. In addition, SIRT6 was a target of miR-92a-3p. miR-92a-3p negatively regulated SIRT6 expression in ox-LDL-induced HUVECs to activate MAPK signaling pathway in vitro. In summary, miR-92a-3p promoted HUVECs apoptosis and suppressed proliferation in ox-LDL-induced HUVECs by targeting SIRT6 expression and activating MAPK signaling pathway.

miR-92a-3p promotes ox-LDL induced-apoptosis in HUVECs via targeting SIRT6 and activating MAPK signaling pathway

Atherosclerosis could be induced by multiple factors, including hypertension, hyperlipidemia, and smoking, and its pathogenesis has not been fully elucidated. MicroRNAs have been shown to possess great anti-atherosclerotic potential, but the precise function of miR-92a-3p in atherosclerosis and its potential molecular mechanism have not been well clarified. Flow cytometry assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazol-3-ium bromide (MTT) assay were performed to evaluate effects of oxidized low-density lipoprotein (ox-LDL) on proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs), respectively. Malondialdehyde and superoxide dismutase levels in cell lysate were assessed with biochemical kits. The expression levels of miR-92a-3p and Sirtuin6 (SIRT6) in HUVECs exposed to ox-LDL were estimated by real-time quantitative polymerase chain reaction (RT-qPCR). In addition, the protein levels of SIRT6, c-Jun N-terminal kinase (JNK), phosphorylation JNK (p-JNK), p38 mitogen activated protein kinase (p38 MAPK), and phosphorylation p38 MAPK (p-p38 MAPK) were measured by western blot assays. The relationship between miR-92a-3p and SIRT6 was confirmed by dual-luciferase reporter assay. Ox-LDL induced apoptosis and oxidative stress in HUVECs in concentration- and time-dependent manners. Conversely, miR-92a-3p silencing inhibited apoptosis and SIRT6 expression in HUVECs. The overexpression of miR-92a-3p enhanced apoptosis and phosphorylation levels of JNK and p38 MAPK as well as inhibited proliferation in ox-LDL-induced HUVECs. In addition, SIRT6 was a target of miR-92a-3p. miR-92a-3p negatively regulated SIRT6 expression in ox-LDL-induced HUVECs to activate MAPK signaling pathway in vitro. In summary, miR-92a-3p promoted HUVECs apoptosis and suppressed proliferation in ox-LDL-induced HUVECs by targeting SIRT6 expression and activating MAPK signaling pathway.

miR-96-5p Regulates Proliferation, Migration, and Apoptosis of Vascular Smooth Muscle Cell Induced by Angiotensin II via Targeting NFAT5.

BACKGROUND: Aberrant proliferation, migration, and apoptosis of vascular smooth muscle cells (VSMCs) are major pathological phenomenon in hypertension. MicroRNAs (miRNAs/miRs) serve crucial roles in the progression of hypertension. We aimed to determine the role of miR-96-5p in the proliferation, migration, and apoptosis of VSMCs and its underlying mechanisms. METHODS: Angiotensin II (Ang II) was employed to treat VSMCs, and the expression of miR-96-5p was detected by RT-qPCR. Then, miR-96-5p mimic was transfected into VSMCs. Cell Counting Kit-8 assay, flow cytometry, transwell assay, and wound healing assay were applied to measure proliferation, cell cycle, and migration of VSMCs. The expression of proteins associated with proliferation, migration, and apoptosis was assessed. A luciferase reporter assay was applied to confirm the target binding between miR-96-5p and nuclear factors of activated T-cells 5 (NFAT5). Subsequently, siRNA was used to silence NFAT5, and cell proliferation, migration, and apoptosis were assessed. RESULTS: The results revealed that the expression of miR-96-5p was downregulated in Ang II-induced VSMCs. MiR-96-5p overexpression inhibited cell proliferation and migration but promoted cell apoptosis, enhanced the percentages of cells in the G1 and G2 phases, and reduced those in the S phase, accompanied by changes in the expression associated proteins. NFAT5 was confirmed as a direct target of miR-96-5p. NFAT5 silencing had the same results with miR-96-5p overexpression on VSMC proliferation, migration, and apoptosis, whereas miR-96-5p inhibitor reversed these effects. CONCLUSIONS: Our findings concluded that miR-96-5p could regulate proliferation, migration, and apoptosis of VSMCs induced by Ang II via targeting NFAT5.

Design, synthesis and evaluation of 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-Based fibrates as potential hypolipidemic and hepatoprotective agents.

Six novel target compounds 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT) based fibrates were synthesized and evaluated. All the synthesized compounds were preliminarily screened by using the Triton WR-1339-induecd hyperlipidemia model, in which T1 exhibited more potent hypolipidemic property than positive drug fenofibrate (FF). T1 also significantly decreased serum triglycerides (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in methionine solution (Mets) induced hyperlipidemic mice. Moreover, hepatic transaminases (AST and ALT) were obviously ameliorated after treatment with T1 and the histological observation indicated that T1 ameliorated the injury in liver tissue and inhibited the hepatic lipid accumulation. In the livers of T1-administrated rat, the levels of PPARα related to lipids metabolism were up-regulated. Additional effects such as antioxidant, anti-inflammatory and H2S releasing action confirmed and reinforced the activity of T1 as a potential multifunctional hypolipidemic and hepatoprotective agent.

Design, synthesis and evaluation of phenylfuroxan nitric oxide-donor phenols as potential anti-diabetic agents.

Both nitric oxide (NO) dysfunction and oxidative stress have been regarded as the important factors in the development and progression of diabetes and its complications. Multifunctional compounds with hypoglycemic, NO supplementation and anti-oxidation will be the promising agents for treatment of diabetes. In this study, six phenylfuroxan nitric oxide (NO) donor phenols were synthesized, which were designed via a combination approach with phenylfuroxan NO-donor and natural phenols. These novel synthetic compounds were screened in vitro for α-glucosidase inhibition, NO releasing, anti-oxidation, anti-glycation and anti-platelet aggregation activity as well as vasodilatation effects. The results exhibited that compound T5 displayed more excellent activity than other compounds. Moreover, T5 demonstrated significant hypoglycemic activity in diabetic mice and oral glucose tolerance test (OGTT) mice. T5 also showed NO releasing and anti-oxidation in diabetic mice. Based on these results, compound T5 deserves further study as potential new multifunctional anti-diabetic agent with antioxidant, NO releasing, anti-platelet aggregation and vasodilatation properties.

A New Series of Salicylic Acid Derivatives as Non-saccharide α-Glucosidase Inhibitors and Antioxidants.

In this study, a series of salicylic acid derivatives were designed and synthesized as novel non-saccharide α-glucosidase inhibitors. Biological evaluation indicated that when compared to acarbose, compounds T9, T10, and T32 exhibited a higher potency of α-glucosidase inhibitory activity with IC50 values of 0.15 ± 0.01, 0.086 ± 0.01 and 0.32 ± 0.02 mM, respectively. Evaluation of the inhibition kinetics indicated that T9, T10, T32, and acarbose interacted with α-glucosidase in a mixed non-competitive inhibitory manner. Moreover, T9, T10, and T32 statically quenched the fluorescence of α-glucosidase by formation of an inhibitor-α-glucosidase complex. The docking results showed that hydrogen bonds were generated between the test compounds and α-glucosidase. The antioxidant study revealed that compound T10 exhibited a higher antioxidant activity via scavenging 1,1-diphenyl-2-picrylhydrazyl free radical (DPPH), thereby inhibiting lipid peroxidation and the total reduction capacity. In brief, the salicylic acid derivatives identified in this study were promising candidates for development as novel non-saccharide α-glucosidase inhibitors.

5-(4-Hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates as potential hypolipidemic and hepatoprotective agents.

Hypolipidemic effects of the newly synthesized 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione-based fibrates were evaluated in Triton WR-1339 and high-fat diet (HFD)-induced hyperlipidemic mice. Preliminary screening of all the synthesized compounds was done by using an acute model (Triton WR-1339 model), in which compound 6 shown more significant antidyslipidemic activity than fenofibrate (FF). The compound 6 was also found to reduce serum triglyceride (TG), total cholesterol (TC) and low density lipoprotein cholesterin (LDL) in HFD-induced hyperlipidemic mice. Moreover, compound 6 displayed hepatoprotective effect, a significant amelioration in hepatic indices (AST and ALT) toxicity was observed and the histological examination showed that compound 6 inhibited the development of hepatic lipid accumulation and ameliorated the damage in hepatic tissue compared to model mice. Additional effects such as the potent antioxidant and anti-inflammatory action confirmed and reinforced the efficacy of compound 6 as a new agent of dual-effect hypolipidemic and hepatoprotective activities.

Synthesis, nitric oxide release, and dipeptidyl peptidase-4 inhibition of sitagliptin derivatives as new multifunctional antidiabetic agents.

Nitric oxide (NO) dysfunction has been found to be an important factor in both the development and progression of diabetic complications due to its many roles in the vascular system. Multifunctional compounds with hypoglycemic and endothelial protective action will be promising agents for the treatment of diabetes and its complications. In this study, a series of novel NO-donating sitagliptin derivatives and relevant metabolites were synthesized and evaluated as potential multifunctional hypoglycemic agents. All of synthetic compounds shown remarkable inhibitory activity against dipeptidyl peptidase IV (DPP-IV) in vitro and demonstrated excellent hypoglycemic activities in diabetic mice, similar to the activity of sitagliptin, and compounds T1-T4 shown different extents of NO-releasing abilities and potent antioxidant abilities in vivo. By screening in DPP-4, compound T4 was recognized as a potent DPP-4 inhibitor with the IC50 value of 0.060 µM. Docking study revealed compound T4 has a favorable binding mode. Furthermore, compounds T1-T4 exhibited different extents of NO-releasing abilities and excellent anti-platelet aggregation in vitro. The overall results suggested that T4 could help to the amelioration of endothelial dysfunction by reducing blood glucose, lessening oxidative stress and raising NO levels as well as inhibiting platelet aggregation. Based on this research, compound T4 deserves further investigation as potential new multifunctional anti-diabetic agent with antioxidant, anti-platelet aggregation and endothelial protective properties.

A new multifunctional hydroxytyrosol-clofibrate with hypolipidemic, antioxidant, and hepatoprotective effects.

Oxidative stress has been regarded as the leading mechanism of the hepatotoxicity of clofibrate (CF). To achieve multifunctional novel hypolipidemic agents with hypolipidemia, antioxidant, and ameliorating liver injury, clofibric acid derivative hydroxytyrosol-clofibrate (CF-HT) was synthesized by molecular hybridization. CF-HT exhibited significant hypolipidemia, reducing serum triglyceride (TG), total cholesterol (TC), and malonaldehyde (MDA) by 30%, 33%, and 29% in hyperlipidemic mice induced by Triton WR 1339. CF-HT also shown hepatoprotective effect, a significant decrease in hepatic indices toxicity was observed, i.e. aspartate and lactate transaminases (AST and ALT) activities, alkalines phosphatases (ALP), and total bilirubin (TBIL) levels. The liver weight and liver coefficient were also ameliorated. Serum superoxide dismutase (SOD) was significantly elevated, and serum catalase (CAT) and malondialdehyde (MDA) content were remarkably restored. The hepatic glutathione (GSH) content was obviously increased and hepatic oxidized glutathione (GSSG) content was reduced dramatically by CF-HT, as compared to the CF treated mice (p < 0.05). Moreover, the histopathological damage that hepatocyte hyperplasia and hypertrophy was also significantly ameliorated by treatment with CF-HT. Therefore, the results indicated that CF-HT exerted more potent hypolipidemic activity and definite hepatoprotective effect which may mainly be associated with its antioxidative property in mice.

Hydroxytyrosol nicotinate, a new multifunctional hypolipidemic and hypoglycemic agent.

Hydroxytyrosol (HT) is a natural polyphenol antioxidant that exists in olive oil. In the study of multifunctional hypolipidemic of nicotinic derivatives, we found that hydroxytyrosol nicotinate (HT-N) incorporation of niacin with HT displayed ?-glucosidase inhibitory activities in vitro, such as yeast ?-glucosidase (IC50?=?117.72??M) and rat intestinal ?-glucosidases maltase (IC50?=?31.86??M) and sucrase (IC50?=?22.99??M), and had a good control of postprandial blood glucose (PBG). HT-N shown significantly hypoglycemic action by 16.9% and protection of pancreatic tissue in type 2 diabetic mellitus (T2DM) mouse model. HT-N also shown a potent antioxidant activity and property of anti-glycation in vitro, which were benefit for ameliorating diabetic complications. Moreover, HT-N exhibited much significant hypolipidemia, lowering plasma triglyceride (TG), total cholesterol (TC), and malonaldehyde (MDA) by 34.6%, 45.8% and 32.1% respectively, in hyperlipidemic mice induced by Triton WR 1339. The results indicated that HT-N has hypolipidemic, hypoglycemic and antioxidant actions. All these properties could be conducive to amelioration of oxidative stress, hyperlipidemia, and diabetes that HT-N may serve as a multifunctional potential therapeutic strategy in diabetic patients with hyperlipidemia.

A new multifunctional hydroxytyrosol-fenofibrate with antidiabetic, antihyperlipidemic, antioxidant and antiinflammatory action.

Dyslipidemia, oxidative stress and inflammation are major risky factors involved in the pathophysiology of type 2 diabetes mellitus and atherosclerosis. Multifunctional intervene is more meaningful. The aim of this study was to evaluate the multifunctional effects of two new compounds, combination of fenofibric acid (FA) with tyrosol (T) or hydroxytyrosol (HT). Compared with fenofibrate (FF), FF-HT exhibited excellent antioxidant capacities in vitro and much improved hypolipidemia, reducing plasma triglyceride (TG), total cholesterol (TC), and malonaldehyde (MDA) by 76%, 54%, and 28%, while FF-T decreased the plasma parameters by 16%, 10%, and 20% in hyperlipidemic mice induced by Triton WR 1339. Furthermore, compound FF-HT exhibited significant antihyperglycemic, antihyperlipidemic, antioxidant and anti-inflammatory activities as well as attenuating hepatotoxicity in a type 2 diabetes experimental mouse model. The histological findings showed that FF-HT suppressed the development of hepatic lipid accumulation and ameliorated the damage in hepatic and pancreatic tissues compared to model mice. This study indicates for the first time that reasonable optimized drug design produce a compound entity which is conducive to the prevention of type 2 diabetes mellitus and its complications.

In vitro evaluation of α-lipoic acid-loaded lipid nanocapsules for topical delivery.

This study aimed at in vitro evaluation of α-lipoic acid-loaded lipid nanocapsules for topical delivery, which was prepared by hot high-pressure homogenisation. Stable particles could be formed and particle size was 148.54 ± 2.31 nm with polydispersity index below 0.15. Encapsulation efficiency and drug loading of α-lipoic acid were 95.23 ± 0.45% and 2.81 ± 0.37%. Antioxidant study showed α-lipoic acid could be protected by lipid nanocapsules without loss of antioxidant activity. Sustained release of α-lipoic acid from lipid nanocapsules was obtained and cumulative release was 62.18 ± 1.51%. In vitro percutaneous study showed the amount of α-lipoic acid distributed in skin was 1.7-fold than permeated. Cytotoxicity assay and antioxidant activity on L929 cells indicated this formulation had low cytotoxicity and ability of protecting cells from oxidative damage within specific concentration. These studies suggested α-lipoic acid-loaded lipid nanocapsules could be potential formulation for topical delivery.

Phenylsulfonylfuroxan NO-donor phenols: Synthesis and multifunctional activities evaluation.

Phenylsulfonyfuroxan nitric oxide (NO)-donor phenols were designed, synthesized and evaluated. The compounds were designed through a symbiotic approach using selected phenols and phenylsulfonylfuroxan NO-donor. The antioxidant activities of the hybrid compounds T2-T6 showed to be good in vivo. Compounds T4 and T6 revealed excellent yeast α-glucosidase inhibitory activity and anti-glycosylation activity. All of the compounds exhibited strong NO releasing activity and significant anti-platelet aggregation activity. The inhibition of platelet aggregation was more than 50% at low concentration (1.5µM) and 95% at higher concentration (15µM and 150µM). The vasodilatation experiment demonstrated that the six compounds under test exhibited definite vasodilation activity (pIC50 ranged from 5.698 to 6.383), especially compound T6 (pIC50 was 6.383) which was similar to sodium nitroprusside (pIC50 was 6.786). Both anticoagulant and vasodilatation effects were correlated with their NO releasing activities. These hybrid phenylsulfonyfuroxan-based NO-donor phenols offer a multifunctional prodrug design concept for the development of therapeutic or preventive agents for metabolic syndrome.

Definition of the binding mode of phosphoinositide 3-kinase α-selective inhibitor A-66S through molecular dynamics simulation.

Activation of the phosphatidylinositol 3-kinase α (PI3Kα) is commonly observed in human cancer and is critical for tumor progression, which has made PI3Kα an attractive target for anticancer drug discovery. To systematically investigate the binding mode of A-66S, a new selective PI3Kα inhibitor for PI3Kα, molecular docking, molecular dynamics simulation and ensuing energetic analysis were performed. The binding free energy between PI3Kα and A-66S is -11.27 kcal•mol⁻¹ using MMPBSA method, while -14.67 kcal•mol⁻¹ using MMGBSA method, which is beneficial for the binding, and the van der Waals/hydrophobic and electrostatic interactions are critical for the binding. The conserved hydrophobic adenine region of PI3Kα made up of Met772, Pro778, Ile800, Tyr836, Ile848, Val850, Val851, Met922, Phe930 and Ile932 accommodates the flat 2-tert-butyl-4'-methyl-4,5'-bithiazol moiety of A-66S, and the NH of Val851 forms a hydrogen with the nitrogen atom embedded in the aminothiazole ring of A-66S. The (S)-pyrrolidine carboxamide urea moiety especially extends toward the region of the binding site wall (Ser854-Gln859) defined by the C-terminal lobe, and has three hydrogen-bond arms with the backbone of Ser854 and the side chain of Gln859. Notably the interaction between the non-conserved residue Gln859 and A-66S is responsible for the selectivity profile of A-66S. The binding mode of A-66S for PI3Kα presented in this study should aid in the design of a new highly selective PI3Kα inhibitor.